Cysteine string protein (CSP) and its role in preventing neurodegeneration

AbstractCysteine string protein (CSP) is a member of the DnaJ/Hsp40 family of co-chaperones that localises to neuronal synaptic vesicles. Its name derives from the possession of a string of 12–15 cysteine residues, palmitoylation of which is required for targeting to post-Golgi membranes. The DnaJ domain of CSP enables it to bind client proteins and recruit Hsc70 chaperones, thereby contributing to the maintenance of protein folding in the presynaptic compartment. Mutation of CSP in flies, worms and mice reduces lifespan and causes synaptic dysfunction and neurodegeneration. Furthermore, recent studies have revealed that the neurodegenerative disease, adult onset neuronal ceroid lipofuscinosis, is caused by mutations in the human CSPα-encoding DNAJC5 gene. Accumulating evidence suggests that the major mechanism by which CSP prevents neurodegeneration is by maintaining the conformation of SNAP-25, thereby facilitating its entry into the membrane-fusing SNARE complex. In this review, we focus on the role of CSP in preventing neurodegeneration and discuss how recent studies of this universal neuroprotective chaperone are being translated into potential novel therapeutics for neurodegenerative diseases

Identification of common genetic modifiers of neurodegenerative diseases from an integrative analysis of diverse genetic screens in model organisms

<p>Abstract</p> <p>Background</p> <p>An array of experimental models have been developed in the small model organisms <it>C. elegans, S. cerevisiae </it>and <it>D. melanogaster </it>for the study of various neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and expanded polyglutamine diseases as exemplified by Huntington's disease (HD) and related ataxias. Genetic approaches to determine the nature of regulators of the disease phenotypes have ranged from small scale to essentially whole genome screens. The published data covers distinct models in all three organisms and one important question is the extent to which shared genetic factors can be uncovered that affect several or all disease models. Surprisingly it has appeared that there may be relatively little overlap and that many of the regulators may be organism or disease-specific. There is, however, a need for a fully integrated analysis of the available genetic data based on careful comparison of orthologues across the species to determine the real extent of overlap.</p> <p>Results</p> <p>We carried out an integrated analysis using <it>C. elegans </it>as the baseline model organism since this is the most widely studied in this context. Combination of data from 28 published studies using small to large scale screens in all three small model organisms gave a total of 950 identifications of genetic regulators. Of these 624 were separate genes with orthologues in <it>C. elegans</it>. In addition, 34 of these genes, which all had human orthologues, were found to overlap across studies. Of the common genetic regulators some such as chaperones, ubiquitin-related enzymes (including the E3 ligase CHIP which directly links the two pathways) and histone deacetylases were involved in expected pathways whereas others such as the peroxisomal acyl CoA-oxidase suggest novel targets for neurodegenerative disease therapy</p> <p>Conclusions</p> <p>We identified a significant number of overlapping regulators of neurodegenerative disease models. Since the diseases have, as an underlying feature, protein aggregation phenotypes it was not surprising that some of the overlapping genes encode proteins involved in protein folding and protein degradation. Interestingly, however, some of the overlapping genes encode proteins that have not previously featured in targeted studies of neurodegeneration and this information will form a useful resource to be exploited in further studies of potential drug-targets.</p

Sense and specificity in neuronal calcium signalling

AbstractChanges in the intracellular free calcium concentration ([Ca2+]i) in neurons regulate many and varied aspects of neuronal function over time scales from microseconds to days. The mystery is how a single signalling ion can lead to such diverse and specific changes in cell function. This is partly due to aspects of the Ca2+ signal itself, including its magnitude, duration, localisation and persistent or oscillatory nature. The transduction of the Ca2+ signal requires Ca2+ binding to various Ca2+ sensor proteins. The different properties of these sensors are important for differential signal processing and determine the physiological specificity of Ca2+ signalling pathways. A major factor underlying the specific roles of particular Ca2+ sensor proteins is the nature of their interaction with target proteins and how this mediates unique patterns of regulation. We review here recent progress from structural analyses and from functional analyses in model organisms that have begun to reveal the rules that underlie Ca2+ sensor protein specificity for target interaction. We discuss three case studies exemplifying different aspects of Ca2+ sensor/target interaction. This article is part of a special issue titled the 13th European Symposium on Calcium

WASH and Tsg101/ALIX-dependent diversion of stress-internalized EGFR from the canonical endocytic pathway

Stress exposure triggers ligand-independent EGF receptor (EGFR) endocytosis, but its post-endocytic fate and role in regulating signalling are unclear. We show that the p38 MAP kinase-dependent, EGFR tyrosine kinase (TK)-independent EGFR internalization induced by ultraviolet light C (UVC) or the cancer therapeutic cisplatin, is followed by diversion from the canonical endocytic pathway. Instead of lysosomal degradation or plasma membrane recycling, EGFR accumulates in a subset of LBPA-rich perinuclear multivesicular bodies (MVBs) distinct from those carrying EGF-stimulated EGFR. Stress-internalized EGFR co-segregates with exogenously expressed pre-melanosomal markers OA1 and fibrillar PMEL, following early endosomal sorting by the actin polymerization-promoting WASH complex. Stress-internalized EGFR is retained intracellularly by continued p38 activity in a mechanism involving ubiquitin-independent, ESCRT/ALIX-dependent incorporation onto intraluminal vesicles (ILVs) of MVBs. In contrast to the internalization-independent EGF-stimulated activation, UVC/cisplatin-triggered EGFR activation depends on EGFR internalization and intracellular retention. EGFR signalling from this MVB subpopulation delays apoptosis and might contribute to chemoresistance

Posttranslational modifications of alpha-tubulin: acetylated and detyrosinated forms in axons of rat cerebellum.

The distribution of acetylated alpha-tubulin in rat cerebellum was examined and compared with that of total alpha-tubulin and tyrosinated alpha-tubulin. From immunoperoxidase-stained vibratome sections of rat cerebellum it was found that acetylated alpha-tubulin, detectable with monoclonal 6-11B-1, was preferentially enriched in axons compared with dendrites. Parallel fiber axons, in particular, were labeled with 6-11B-1 yet unstained by an antibody recognizing tyrosinated alpha-tubulin, indicating that parallel fibers contain alpha-tubulin that is acetylated and detyrosinated. Axonal microtubules are known to be highly stable and the distribution of acetylated alpha-tubulin in other classes of stable microtubules suggests that acetylation and possibly detyrosination may play a role in the maintenance of stable populations of microtubules

Neuronal calcium sensor proteins: emerging roles in membrane traffic and synaptic plasticity

Ca2+ plays a crucial role in the regulation of neuronal function. Recent work has revealed important functions for two families of neuronally expressed Ca2+ sensor proteins. These include roles in membrane traffic and in alterations in synaptic plasticity underlying changes in behaviour

A major role for protein kinase C in calcium-activated exocytosis in permeabilised adrenal chromaffin cells

AbstractThe role of endogenously activated protein kinase C in calcium-activated exocytosis was examined in digitonin-permeabilised bovine adrenal chromaffin cells. Protein kinase C activity was reduced by down-regulation following long-term treatment with PMA or by using the inhibitor sphingosine. Both treatments resulted in a substantial reduction in catecholamine secretion elicited by micromolar calcium, indicating that endogenous activation of protein kinase C is a major requirement for calcium-activated exocytosis in chromaffin cells

Learning Timbre Analogies from Unlabelled Data by Multivariate Tree Regression

This is the Author's Original Manuscript of an article whose final and definitive form, the Version of Record, has been published in the Journal of New Music Research, November 2011, copyright Taylor & Francis. The published article is available online at http://www.tandfonline.com/10.1080/09298215.2011.596938

Від шляхетства до дворянства: до історії польської присутності на Ніжинщині в ХVІІ – першій третині ХІХ століття (за матеріалами формулярних списків)

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Dynamics and calcium sensitivity of the Ca2+/myristoyl switch protein hippocalcin in living cells

Hippocalcin is a neuronal calcium sensor protein that possesses a Ca2+/myristoyl switch allowing it to translocate to membranes. Translocation of hippocalcin in response to increased cytosolic [Ca2+] was examined in HeLa cells expressing hippocalcin–enhanced yellow fluorescent protein (EYFP) to determine the dynamics and Ca2+ affinity of the Ca2+/myristoyl switch in living cells. Ca2+-free hippocalcin was freely diffusible, as shown by photobleaching and use of a photoactivable GFP construct. The translocation was dependent on binding of Ca2+ by EF-hands 2 and 3. Using photolysis of NP-EGTA, the maximal kinetics of translocation was determined (t1/2 = 0.9 s), and this was consistent with a diffusion driven process. Low intensity photolysis of NP-EGTA produced a slow [Ca2+] ramp and revealed that translocation of hippocalcin–EYFP initiated at around 180 nM and was half maximal at 290 nM. Histamine induced a reversible translocation of hippocalcin–EYFP. The data show that hippocalcin is a sensitive Ca2+ sensor capable of responding to increases in intracellular Ca2+ concentration over the narrow dynamic range of 200–800 nM free Ca2+